The oral, investigational, small-molecule BCL-2 inhibitor venetoclax has shown excellent and durable responses in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). All patients in the trial harbored the 17p deletion (del 17p), which signals poor prognosis.
In the pivotal phase 2 trial reported at ASH 2015, nearly 80% of high-risk patients with relapsed or refractory CLL had a response to venetoclax monotherapy, approximately 10% had a complete response and partial response, and more than 20% had minimal residual disease; the responses were durable.
So far, 3 other new drugs have been approved by the FDA for the treatment of patients with CLL, including the Bruton’s kinase inhibitor ibrutinib (Imbruvica), the PI3K inhibitor idelalisib (Zydelig), and the anti-CD20 obinutuzumab (Gazyva), which is a more potent version of rituximab (Rituxan).
Venetoclax attacks CLL by a different mechanism, inhibiting the BCL-2 protein that prevents cell death, making it an attractive partner with other CLL drugs that have a complementary mechanism of action.
Venetoclax has such strong antitumor activity that tumor lysis syndrome (TLS) emerged as a major concern in preliminary studies. This led AbbVie (one of the study’s sponsors) and the investigators to adjust the dosing schedule of venetoclax, initiating treatment at 20 mg daily and increasing the dose slowly over 4 weeks to a target dose of 400 mg daily. The new dosing schedule has not led to any clinical TLS, but there has been laboratory evidence of TLS in approximately 20% of patients in various trials.
“We saw deep responses and acceptable toxicity with venetoclax monotherapy in a relapsed/refractory population. Investigator-confirmed complete response was 7.5% and nodular partial response was 2.8%, with minimal disease negativity in greater than 20%,” said Stephan Stilgenbauer, MD, PhD, Department of Internal Medicine III, University of Ulm, Germany.
“In this study, venetoclax had a favorable risk–benefit profile. The risk of tumor lysis syndrome was effectively mitigated by our careful dosing strategy, and we saw no clinical tumor lysis syndrome,” Dr Stilgenbauer said.
This pivotal study enrolled 107 patients with relapsed or refractory CLL and del 17p confirmed by a central laboratory. The median progression-free survival (PFS) with frontline chemotherapy is <12 months, Dr Stilgenbauer noted.
At baseline, the median patient age was 67 years; the median number of previous therapies was 2, and approximately 50% had received previous bendamustine (Treanda) at relapse. Approximately 42% of patients were considered to be at high risk for TLS.
The median time on study was 12.1 months; 37 patients discontinued venetoclax because of disease progression, and 9 because of adverse events. There were 18 deaths, 14 of which resulted from progressive disease.
The primary end point of overall response rate was 79.4%.
Only 4 of 87 patients with baseline lymphocytosis did not achieve normalized absolute lymphocyte count with venetoclax therapy.
The median time to first response was <1 month, and venetoclax achieved durable responses. The median time to response was not reached at the time of the ASH 2015 meeting.
The 12-month estimated PFS rate was 72%; although it had not been reached yet, the estimated overall survival rate was 86.7%.
The most common adverse events were low-grade neutropenia, anemia, and thombocytopenia. Serious adverse events were reported in 55% of patients.
Venetoclax is also being studied in combination with other drugs in CLL.